Abstract Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-2% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis, cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible for women at risk for losing ovarian function, yet there is a great need for robust and better biomarkers capable of predicting ovarian insufficiency. We are interested in identifying genetic biomarkers that associate with POI. The role of the X chromosome and candidate autosomal genes implicated from knockout animal models has been hypothesized for a long time in the etiology of human POI, yet there is little to show at the gene level. We constructed a novel high-resolution genomic array that interrogates the X chromosome and 134 candidate autosomal gene copy numbers. We show that this array can detect genomic imbalances as small as 500 base pairs, and is superior to commercial arrays. We hypothesize that pathologic genomic imbalances involving the X chromosome and candidate autosomal loci, will be present in more than 10% of women who suffer POI. Moreover, we will sequence the X-chromosome exomes, as well as the exomes of 134 candidate autosomal genes to define contribution of pathogenic mutations to POI. Our proposal will test the relevance of our targeted approach in identifying pathogenic mutations in women with POI, and will stimulate further research into the feasibility of such targeted approaches to predict ovarian failure. Proposed studies may identify novel pathways, and provide future directions for basic science investigations relevant to human POI.